Inhibition of Fibril Formation by Tyrosine Modification of Diphenylalanine: Crystallographic Insights

Abstract

The self-assemblies of diphenylalanine and its tyrosine analogues have been investigated. The peptide Boc-Phe-Phe-OMe (1), having a sequence identity with the central hydrophobic cluster (CHC) of Alzheimer’s β-amyloid diphenylalanine motif, self-assembles to produce twisted fibrils. In contrast, the tyrosine-modified analogues Boc-Phe-Tyr-OMe (2), Boc-Tyr-Phe-OMe (3), and Boc-Tyr-Tyr-OMe (4), self-assemble to form microspheres. The X-ray crystallography reveal that the peptide 1 adopts an inverse γ-turn structure and self-associates as a hydrogen-bonded chain of molecules along a 2-fold screw axis, whereas the tyrosine-modified analogues exhibit parallel β-sheet aggregation and cyclic packing in higher-order assembly. The structural analysis of the peptides as described here can serve as a basis for de novo design and therapeutics.